Chloroimidazolium Deoxyfluorination Reagent with H2F3– Anion as a Sole Fluoride Source

In the study, we introduce an air-stable NHC-based deoxyfluorination reagent ImCl[H2F3], offering a promising avenue for deoxyfluorination across various substrates. Reagent efficiently fluorinates benzyl alcohols, carboxylic acids, and P(V) compounds without external fluoride sources. A mechanistic study reveals a two-step process involving benzyl chloride as an intermediate, shedding light on the two-step reaction pathway. The Hammet plot provides insights into reaction mechanisms with different substrates, enhancing our understanding of this versatile deoxyfluorination method.


Instrumentation and materials
All chemicals, materials and solvents were purchased from commercial sources and used without further purification unless otherwise noted.Solvents (PhMe, Et2O, MeCN) were distilled over sodium wire and then stored over 3 Å molecular sieves (20% v/v) for at least 72 hours prior to use. 1 H, 19 F, 31 P and 13 C{ 1 H} NMR spectra were recorded on a Bruker Avance III 500 MHz NMR spectrometer (500 MHz for 1 H, 471 MHz for 19 F and 126 MHz for 13 C) and Bruker Ascend 600 MHz NMR spectrometer.Chemical shifts were reported as delta scale in ppm relative to CDCl3 (residual CHCl3 δ = 7.26 ppm for 1 H, 77.16 ppm for 13 C).CCl3F for 19 F (δ = 0.00 ppm) and H3PO4 for 31 P (δ = 0.00 ppm).Proton magnetic resonance spectra ( 1 H NMR) were recorded with 10 second delay between scans to ensure accurate integration.High-resolution Atmospheric Pressure Chemical Ionization Time-of-Flight Mass (HR-APCI-TOF-MS) spectra were recorded on an Agilent 6224 Accurate Mass TOF LC/MS System.Reagent 1 was prepared according to literature procedure and stored in ambient conditions.Prior to use 1 was dried at 70 °C under vacuum. 1 Phosphinates 6b−e were prepared according to modified procedure. 2

General procedures for preparation of fluorides with reagent 1
Benzyl fluorides; General procedure A Benzyl alcohol 2a−p (0.1 mmol) and naphthalene (1.0 eq., 0.1 mmol as internal standard) were dissolved in dry MeCN (1 mL, 0.1 M) in a glass vial.Reagent 1 (2.0 eq., 97 mg, 0.2 mmol) was added and the solution was stirred for 1 min until full dissolution.BTMG (4.0 eq., 0.4 mmol, 68.5 mg) was added in one portion, the vial was sealed with a Teflon lined stopper and heated in an aluminum heating block at 100 °C for 3 h.After that, the reaction was let to cool to room temperature and 10 µL was transferred to a dry NMR tube and 500 µL of CDCl3 was added.

Acyl fluorides; General procedure B
Carboxylic acids 4a−ad (0.1 mmol) and naphthalene (1.0 eq., 0.1 mmol as internal standard) were dissolved in dry MeCN (1 mL, 0.1 M) in a glass vial.Reagent 1 (1.1 eq., 48.3 mg, 0.1 mmol) was added and the solution was stirred for 1 min until full dissolution.DIPEA (2.0 eq., 0.2 mmol, 26 mg) was added in one portion, the vial was sealed with a Teflon lined stopper and stirred at rt for 1 h.After that, 10 µL was transferred to a dry NMR tube and 500 µL of CDCl3 was added.

Fluorophosphates and phosphinates; General procedure C
Phosphates or phosphinates 6a−k (0.1 mmol) and naphthalene (1.0 eq., 0.1 mmol as internal standard) were dissolved in dry MeCN (1 mL, 0.1 M) in a glass vial.Reagent 1 (2.0 eq., 97 mg, 0.2 mmol) was added and the solution was stirred for 1 min until full dissolution.BTMG (4.0 eq., 0.4 mmol, 68.5 mg) was added in one portion, the vial was sealed with a Teflon lined stopper and stirred at rt for 1 h.After that, 10 µL was transferred to a dry NMR tube and 500 µL of CDCl3 was added.
Caution! Organo phosphates are potentially extremely toxic!Fluoroorgano phosphates are known neurotoxins!Reactions were performed in a fume hood and residues were diluted with NaOH solution and disposed of properly!Larger scale (1 mmol) synthesis of 4-methylbenzyl fluoride 3l 4-methylbenzyl alcohol 2l was dissolved in dry MeCN (10 mL, 0.1 M) in a Teflon™ reactor.Reagent 1 (2.2 eq., 483 mg, 2.2 mmol) was added and the solution was stirred for 1 min until full dissolution.DIPEA (6.0 eq., 6 mmol, 774 mg) was added in one portion, the reactor was heated in an oil bath at 140 °C for 24 h.The product was isolated by the following procedure: the solvent was evaporated, and the residue was dissolved in n-pentane.The product was purified by silica gel column flash chromatography using n-pentane as eluent (mixture of 4-methylbenzyl fluoride 3l and 4-methylbenzyl chloride 70:30, clear liquid).The ratio was determined with 1 H NMR. The mass of the product after evaporation of the solvent was 100 mg (78% yield).

Mechanistic study experiments
In the first step of the reaction benzyl chloride I is formed.This step is fast and most of the starting material is consumed within minutes of the addition of the base.The second step of the reaction involves SN2 reaction of the benzyl chloride to yield benzyl fluoride.This step is considerably slower and requires elevated temperatures (Table S-4).

Benzoic acids
Benzoic acid 4a (0.1 mmol) and one of the substituted benzoic acids 4c, 4d, 4e, 4f, 4g, 4i, 4j, 4k (1 eq., 0.1 mmol) were dissolved in dry MeCN (1 mL, 0.1 M) in a glass vial.Reagent 1 (1 eq., 48 mg, 0.1 mmol) was added, and the solution was stirred for 1 min until full dissolution.DIPEA (2 eq., 0.2 mmol, 34.3 mg) was added in one portion, the vial was sealed with a Teflon lined stopper and stirred at room temperature for 0.5 h.After that 10 µL was transferred to a dry NMR tube and 500 µL of CDCl3 was added.The ratio XX/XH between fluorinated products was determined based on the integration ratios of the aromatic signals.Plot of log(XX/XH) values against corresponding σ values was plotted.A line (R 2 = 0.945) with ρ = −2.55 was obtained.

Phosphinic acids
Diphenylphosphinic acid 6a (0.1 mmol) and substituted diphenylphosphinic acids 6b, 6c, 6d, 6e (1.0 eq., 0.1 mmol) were dissolved in dry MeCN (1 mL, 0.1 M) in a glass vial.Reagent 1 (1.0 eq., 48 mg, 0.1 mmol) was added, and the solution was stirred for 1 min until full dissolution.DIPEA (2.0 eq., 0.2 mmol, 25.8 mg) was added in one portion, the vial was sealed with a Teflon lined stopper and stirred at room temperature for 1 h.After that 10 µL was transferred to a dry NMR tube and 500 µL of CDCl3 was added.The ratio XX/XH between fluorinated products was determined with 19 F NMR. Plot of log(XX/XH) values against corresponding σ values was plotted.A line (R 2 = 0.989) with ρ = -2.0 was obtained.

Spectroscopic data for benzyl fluorides
Example of NMR yield determination and purity of compounds.NMR yield was determined with naphthalene as an internal standard.Wight amount of standard was added prior to all the reagents and its integral calculated.Benzyl fluoride (3a) Prepared according to general procedure A for benzyl alcohols.Yield was determined with 1 H NMR with naphthalene as an internal standard (6.39 mg, 58%). 1 H NMR (600 MHz, CDCl3, 25 °C): δ 7.42-7.37(m, 5H), 5.39 (d, J = 47.8Hz, 2H). 19F NMR (565 MHz, CDCl3, 25 °C): δ -206.6 (t, J = 47.7 Hz).Spectroscopic data matched those previously reported in literature. 3tert-butylbenzyl fluoride (3b) Prepared according to general procedure A for benzyl alcohols.Yield was determined with 1 H NMR with naphthalene as an internal standard (10.47 mg, 63%). 1 19 F NMR (565 MHz, CDCl3, 25 °C): δ -112.9 (m), -203.9 (t, J = 48. 2 Hz).Spectroscopic data matched those previously reported in literature. 11trifluoromethylthiobenzyl fluoride (3k) Prepared according to general procedure A for benzyl alcohols.Yield was determined with 1 H NMR with naphthalene as an internal standard (17.24mg, 82%).The product was isolated by the following procedure: The solvent was evaporated, and the residue was dissolved in a mixture of aqueous HCl 0.5 M (15 mL) and dichloromethane (15 mL).After phase separation, the solvent from organic phase was evaporated and the product was purified by silica gel column flash chromatography using hexane and dichloromethane (3:2) as eluent (mixture of 4-trifluoromethylthiobenzyl fluoride 3k and 4trifluoromethylthiobenzyl chloride 1 : 1.7, clear liquid).

Table S - 1 :
Optimization of reaction conditions for fluorination of benzyl alcohols with reagent 1

Table S -3: Optimization
of reaction conditions for fluorination of phosphates and phosphinates with reagent 1
Prepared according to general procedure B for benzoic acids.Yield was determined with 1 H NMR with naphthalene as an internal standard (14.27mg, 90%).